Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb

Cathryn Broderick; Lorna Watson; Matthew P Armon

doi:10.1002/14651858.CD002783.pub5

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Funnel plot of comparison: 1 Thrombolysis versus standard anticoagulation, outcome: 1.4 Bleeding (early, subgrouped by thrombolysis strategy).

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Analysis 1.1

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 1: Complete clot lysis (early, subgrouped by thrombolysis strategy)

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Analysis 1.2

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 2: Complete clot lysis (intermediate, subgrouped by thrombolysis strategy)

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Analysis 1.3

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 3: Complete clot lysis (late, subgrouped by thrombolysis strategy)

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Analysis 1.4

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 4: Bleeding (early, subgrouped by thrombolysis strategy)

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Analysis 1.5

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 5: PTS (intermediate, subgrouped by thrombolysis strategy)

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Analysis 1.6

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 6: PTS by iliofemoral/fempop (intermediate, subgrouped by location)

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Analysis 1.7

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 7: PTS (late, subgrouped by thrombolysis strategy)

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Analysis 1.8

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 8: Any improvement in venous patency (early)

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Analysis 1.9

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 9: Stroke (early, subgrouped by thrombolysis strategy)

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Analysis 1.10

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 10: Leg ulceration (intermediate, subgrouped by thrombolysis strategy)

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Analysis 1.11

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 11: Leg ulceration (late)

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Analysis 1.12

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 12: Mortality (early, subgrouped by thrombolysis strategy)

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Analysis 1.13

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 13: Mortality (intermediate, subgrouped by thrombolysis strategy)

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Analysis 1.14

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 14: Mortality (late, subgrouped by thrombolysis strategy)

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Analysis 1.15

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 15: Recurrent DVT (intermediate, subgrouped by thrombolysis strategy)

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Analysis 1.16

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 16: Recurrent DVT (late, subgrouped by thrombolysis strategy)

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Analysis 1.17

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 17: Pulmonary embolism (early, subgrouped by thrombolysis strategy)

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Analysis 1.18

Comparison 1: Thrombolysis versus standard anticoagulation, Outcome 18: Venous function (intermediate, subgrouped by thrombolysis strategy)

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Summary of findings 1. Treatment with any thrombolysis strategy for acute deep vein thrombosis

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Treatment with any thrombolysis clot removal strategy for acute DVT
Patient or population: patients diagnosed with acute DVT Setting: hospital Intervention: thrombolysis¹ Comparison: standard anticoagulation
Outcomes	Risk with standard anticoagulation	Risk with thrombolysis	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Complete clot lysis (intermediate, 6 months to under 5 years after treatment)	Study population		RR 2.42 (1.42 to 4.12)	654 (7 RCTs)	⊕⊕⊕⊝ MODERATE ²	78 of 244 patients treated with standard anticoagulation had complete clot lysis compared to 198 of 410 in the thrombolysis group
	320 per 1000	774 per 1000 (454 to 1000)	RR 2.42 (1.42 to 4.12)	654 (7 RCTs)	⊕⊕⊕⊝ MODERATE ²
Bleeding (early, up to 1 month after treatment)	Study population		RR 2.45 (1.58 to 3.78)	1943 (19 RCTs)	⊕⊕⊕⊝ MODERATE ³
Bleeding (early, up to 1 month after treatment)	23 per 1000	56 per 1000 (36 to 87)	RR 2.45 (1.58 to 3.78)	1943 (19 RCTs)	⊕⊕⊕⊝ MODERATE ³
Post‐thrombotic syndrome (intermediate, 6 months to under 5 years after treatment)	Study population		RR 0.78 (0.66 to 0.93)	1393 (6 RCTs)	⊕⊕⊕⊝ MODERATE ²	329 of 622 patients treated with standard anticoagulation developed PTS compared to 383 of 771 treated with thrombolysis. Additional subgroup analysis did not show any differences in PTS incidence between iliofemoral and femoropopliteal DVTs
	529 per 1000	413 per 1000 (349 to 492)	RR 0.78 (0.66 to 0.93)	1393 (6 RCTs)	⊕⊕⊕⊝ MODERATE ²
Post‐thrombotic syndrome (late, 5 years follow‐up after treatment)	Study population		RR 0.56 (0.43 to 0.73)	211 (2 RCTs)	⊕⊕⊕⊝ MODERATE ²	75 of 107 patients treated with standard anticoagulation developed PTS compared to 41 of 104 treated with thrombolysis
	701 per 1000	393 per 1000 (301 to 512)	RR 0.56 (0.43 to 0.73)	211 (2 RCTs)	⊕⊕⊕⊝ MODERATE ²
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CDT: catheter‐directed thrombolysis; CI: confidence interval; DVT: deep vein thrombosis; PTS: post‐thrombotic syndrome; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Thrombolysis includes delivery of thrombolytics either systemically, loco‐regionally or by CDT. CDT may include the use of additional endovascular techniques ²Downgraded by one level as the number of participants in the majority of studies included in the analysis is small ³Downgraded by one level as the number of participants and events in the majority of studies included in the analysis is small (only 4/19 studies had over 100 participants)

Summary of findings 1. Treatment with any thrombolysis strategy for acute deep vein thrombosis

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Table 1. Level of affected leg veins in included studies

Study	Potential levels of leg vein included
Arnesen 1978	proximal to calf
ATTRACT	proximal (femoral, common femoral, iliac vein with or without other involved ipsilateral veins)
CAVA 2020	femoral and iliofemoral
CAVENT	pelvic, iliofemoral, femoral
Common 1976	not specified
Elliot 1979	proximal
Elsharawy 2002	femoral and iliofemoral
Goldhaber 1990	popliteal or more proximal
Goldhaber 1996	proximal
Kakkar 1969	not specified
Kiil 1981	not specified
Marder 1977	calf up to iliac vein
Schulman 1986	calf vein thrombosis only
Schweizer 1998	not specified
Schweizer 2000	leg or pelvic (popliteal or more proximal)
Tsapogas 1973	not specified
Turpie 1990	proximal
Ugurlu 2002	popliteal up to inferior vena cava
Verhaeghe 1989	popliteal or more proximal

Table 1. Level of affected leg veins in included studies

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Comparison 1. Thrombolysis versus standard anticoagulation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Complete clot lysis (early, subgrouped by thrombolysis strategy) Show forest plot	8	592	Risk Ratio (M‐H, Random, 95% CI)	4.75 [1.83, 12.33]

1.1.1 Systemic	7	432	Risk Ratio (M‐H, Random, 95% CI)	3.65 [1.40, 9.56]
1.1.2 Loco‐regional	1	125	Risk Ratio (M‐H, Random, 95% CI)	10.55 [0.66, 168.79]
1.1.3 CDT	1	35	Risk Ratio (M‐H, Random, 95% CI)	21.79 [1.38, 343.26]
1.2 Complete clot lysis (intermediate, subgrouped by thrombolysis strategy) Show forest plot	7	654	Risk Ratio (M‐H, Random, 95% CI)	2.42 [1.42, 4.12]

1.2.1 Systemic	4	239	Risk Ratio (M‐H, Random, 95% CI)	3.80 [1.46, 9.93]
1.2.2 Loco‐regional	2	191	Risk Ratio (M‐H, Random, 95% CI)	1.75 [1.03, 2.97]
1.2.3 CDT	2	224	Risk Ratio (M‐H, Random, 95% CI)	2.52 [0.52, 12.17]
1.3 Complete clot lysis (late, subgrouped by thrombolysis strategy) Show forest plot	2	206	Risk Ratio (M‐H, Random, 95% CI)	3.25 [0.17, 62.63]

1.3.1 Systemic	1	34	Risk Ratio (M‐H, Random, 95% CI)	16.76 [1.03, 272.11]
1.3.2 Loco‐regional	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.3.3 CDT	1	172	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.94, 1.33]
1.4 Bleeding (early, subgrouped by thrombolysis strategy) Show forest plot	19	1943	Risk Ratio (M‐H, Fixed, 95% CI)	2.45 [1.58, 3.78]

1.4.1 Systemic	14	685	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [1.24, 3.19]
1.4.2 Loco‐regional	2	191	Risk Ratio (M‐H, Fixed, 95% CI)	3.07 [0.41, 23.05]
1.4.3 CDT	4	1067	Risk Ratio (M‐H, Fixed, 95% CI)	7.30 [1.67, 31.98]
1.5 PTS (intermediate, subgrouped by thrombolysis strategy) Show forest plot	6	1393	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.66, 0.93]

1.5.1 Systemic	2	170	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.31, 0.92]
1.5.2 Loco‐regional	2	191	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.73, 1.07]
1.5.3 CDT	3	1032	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.74, 1.05]
1.6 PTS by iliofemoral/fempop (intermediate, subgrouped by location) Show forest plot	6	1393	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.71, 0.94]

1.6.1 Iliofemoral DVT	4	777	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.55, 1.01]
1.6.2 Femoropopliteal DVT	1	300	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.76, 1.27]
1.6.3 Unspecified DVT	2	316	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.69, 0.92]
1.7 PTS (late, subgrouped by thrombolysis strategy) Show forest plot	2	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.43, 0.73]

1.7.1 Systemic	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.14, 0.88]
1.7.2 loco‐regional	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.7.3 CDT	1	176	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.45, 0.79]
1.8 Any improvement in venous patency (early) Show forest plot	9	421	Risk Ratio (M‐H, Random, 95% CI)	2.48 [1.35, 4.57]

1.8.1 Systemic	8	386	Risk Ratio (M‐H, Random, 95% CI)	2.18 [1.28, 3.70]
1.8.2 CDT	1	35	Risk Ratio (M‐H, Random, 95% CI)	35.05 [2.28, 539.63]
1.9 Stroke (early, subgrouped by thrombolysis strategy) Show forest plot	19	1943	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [0.34, 10.86]

1.9.1 Systemic	14	685	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [0.34, 10.86]
1.9.2 Loco‐regional	2	191	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.9.3 CDT	4	1067	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.10 Leg ulceration (intermediate, subgrouped by thrombolysis strategy) Show forest plot	5	1033	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.39, 1.49]

1.10.1 Systemic	2	87	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.53]
1.10.2 Loco‐regional	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.17, 13.60]
1.10.3 CDT	2	880	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.36, 1.54]
1.11 Leg ulceration (late) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.12 Mortality (early, subgrouped by thrombolysis strategy) Show forest plot	10	1220	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.31, 1.89]

1.12.1 Systemic	8	369	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.31, 1.89]
1.12.2 Loco‐regional	1	125	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.12.3 CDT	2	726	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.13 Mortality (intermediate, subgrouped by thrombolysis strategy) Show forest plot	4	1144	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.39, 1.69]

1.13.1 Systemic	2	176	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.27, 3.43]
1.13.2 Loco‐regional	1	125	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.13.3 CDT	2	843	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.31, 1.86]
1.14 Mortality (late, subgrouped by thrombolysis strategy) Show forest plot	2	230	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.25, 1.50]

1.14.1 Systemic	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.34, 5.24]
1.14.2 CDT	1	188	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.10, 1.30]
1.15 Recurrent DVT (intermediate, subgrouped by thrombolysis strategy) Show forest plot	4	1067	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.96, 1.83]

1.15.1 Systemic	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.37, 5.40]
1.15.2 Loco‐regional	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.15.3 CDT	3	1032	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.94, 1.84]
1.16 Recurrent DVT (late, subgrouped by thrombolysis strategy) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.16.1 Systemic	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.16.2 CDT	1	176	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.34, 1.18]
1.17 Pulmonary embolism (early, subgrouped by thrombolysis strategy) Show forest plot	6	433	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.33, 3.05]

1.17.1 Systemic	5	273	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.36, 4.10]
1.17.2 Loco‐regional	1	125	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.17.3 CDT	1	35	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.26]
1.18 Venous function (intermediate, subgrouped by thrombolysis strategy) Show forest plot	3	255	Risk Ratio (M‐H, Random, 95% CI)	2.18 [0.86, 5.54]

1.18.1 Systemic	1	31	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.59, 1.83]
1.18.2 Loco‐regional	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.18.3 CDT	2	224	Risk Ratio (M‐H, Random, 95% CI)	3.18 [1.41, 7.19]

Comparison 1. Thrombolysis versus standard anticoagulation

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